For more than half a century amphotericin B (AmB) has served as the gold standard for treating systemic fungal infections. AmB has a broad spectrum of activity, is fungicidal, and is effective even against fungal strains that are resistant to multiple other agents.[1] Surprisingly, clinically significant microbial resistance has remained exceptionally rare[2] while resistance to next generation antifungals has appeared within just a few years of their clinical introduction.[2e, 3] Unfortunately, AmB is also highly toxic.[4] Thus, the effective treatment of systemic fungal infections is all too often precluded, not by a lack of efficacy, but by dose-limiting side effects.[5] Some progress has been made using liposome delivery systems,[6] but these treatments are prohibitively expensive[7] and significant toxicities remain.[8] Thus, a less toxic, but equally effective AmB derivative stands to have a major impact on human health.